Sevofluran ve/veya Deksmedetomidin'in Sıçan Yavrularında Davranış, Nöroinflamasyon ve Apoptoz Üzerindeki Etkilerinin Karşılaştırmalı Değerlendirilmesi

Öz

Giriş: Gelişen beyin anesteziklerin yan etkilerine karşı savunmasızdır. Birçok türde nörotoksik ve bilişsel değişiklikler belgelenmiştir ve küçük çocukların uzun süreler veya tekrar tekrar inhalasyon anestezisine maruz kalmaları durumunda olumsuz etkilenebileceği endişesi vardır. Bu deneyde sevofluranın (SEVO) davranışsal ve nörotoksik etkilerini değerlendirmeyi amaçlıyoruz. ve/veya yavru sıçanlarda deksmedetomidin (DEX) maruziyeti. Gereç ve Yöntem: Postnatal 21 günlük 36 rat rastgele 6 gruba ayrıldı (Grup I (kontrol); Grup II: 4 saatlik %2,5 SEVO; Grup III: 4 saatlik %2,5 SEVO+intraperitoneal (i.p.) 0,5 µg). kg-1 DEX; Grup IV: 4 saat için %2,5 SEVO+i.p. 5 µg.kg-1 DEX; Grup V: i.p. 0.5 µg.kg-1 DEX; Grup VI: i.p. 5 µg.kg-1 DEX verildi) . Sıçanların davranışları modifiye Radial Arm Maze testi ile incelendi. Yavruların sıçan beyninin nöroinflamasyon ve apoptoz için histopatolojik değerlendirmesi yapıldı. İstatistiksel değerlendirme SPSS 20.0 kullanılarak yapıldı, P değeri <0,05 istatistiksel olarak anlamlı kabul edildi. Bulgular: Sıçanlarda erken yaşam döneminde 4 saat boyunca tek seferlik %2,5 SEVO maruziyeti histolojik olarak beyin dokusunda nöroinflamasyon belirtileri göstermemekle birlikte davranış testinde öğrenme ve hafızada bozulmaya yol açmıştır (P<0,05). Beyin dokusunun CA3 aşamasında apoptoz yüzdesi SEVO+DEX gruplarında kontrol ve tek SEVO grupları ile karşılaştırıldığında azaldı (P<0.05). Sonuç: SEVO'ya DEX eklenmesi, hafıza ve öğrenme işlevinde daha az bozulmaya neden oldu. Ancak tek 5 µg.kg-1 DEX, öğrenme ve hafıza işlevini olumsuz etkiledi, ancak lokomotor aktiviteyi ve kaygıyı etkilemedi.

Anahtar Kelimeler

• sevofluran
• deksmedetomidin
• yavru fareler
• nörotoksik
• kognitif değişiklikler

Comparative Evaluation of the Effects of Sevoflurane and/or Dexmedetomidine on Behavior, Neuro-inflammation and Apoptosis in Pups Rat

Öz

Aim: Developing brain is vulnerable to side effects of anesthetics. Neurotoxic and cognitive alterations have been documented in several species, and there is concern that small children could be affected adversely if they are exposed for long periods or recurrently to inhalation anesthesia In this experiment we aim to evaluate behavioral and neurotoxic effects of sevoflurane (SEVO) and/or dexmedetomidine (DEX) exposure in pup rats. Materials and method: Postnatal 21 days old 36 rat were randomly divided into 6 groups (Group I (control); Group II:2.5% SEVO for 4 hours; Group III:2.5% SEVO for 4 hours+intraperitoneal (i.p.) 0.5 µg.kg-1 DEX; Group IV:2.5% SEVO for 4 hours+i.p. 5 µg.kg-1 DEX; Group V: i.p. 0.5 µg.kg-1 DEX; Group VI: i.p. 5 µg.kg-1 DEX was given). Behavior of the rat were examined with the modified Radial Arm Maze test. Histopathological evaluation of the pups’ rat brain for neuroinflammation and apoptosis was performed. Statistical evaluation was carried out using the SPSS 20.0, P value <0.05 was considered statistically significant. Results: Single 2.5% SEVO exposure for 4 hours during early life period in rats is although not show neuroinflammation signs the brain tissue histologically but impaired learning and memory in behavior test (P<0.05). In CA3 stage of the brain tissue apoptosis percentage was diminished in SEVO+DEX groups for comparison with control and single SEVO groups (P<0.05). Conclusions: Adding DEX to SEVO caused less impairment in memory and learning function. But single 5 µg.kg-1 DEX negatively affected learning and memory function but not locomotor activity and anxiety.

Anahtar Kelimeler

• sevoflurane
• dexmedetomidine
• pup rats
• Neurotoxic
• cognitive alterations

Kaynakça

1. 1. Andropoulos DB Effect of Anesthesia on the Developing Brain: Infant and Fetus. Fetal Diagn Ther 2018; 43:1-11.
2. 2. Yang F, Zhao H, Zhang K, et al. Research progress and treatment strategies for anesthetic neurotoxicity. Brain Res Bull 2020; 164:37-44.
3. 3. Delgado‐Herrera L, Ostroff RD, Rogers SA Sevoflurance: approaching the ideal inhalational anesthetic. a pharmacologic, pharmacoeconomic, and clinical review. CNS Drug Rev 2001; 7:48-120.
4. 4. Brohan J, Goudra BG. The Role of GABA Receptor Agonists in Anesthesia and Sedation. CNS Drugs 2017; 31:845-56.
5. 5. Sottas CE, Anderson BJ. Dexmedetomidine: the new all-in-one drug in paediatric anaesthesia?. Curr Opin Anaesthesiol 2017; 30:441-51.
6. 6. Wang X, Shan Y, Tang Z, et al. Neuroprotective effects of dexmedetomidine against isoflurane-induced neuronal injury via glutamate regulation in neonatal rats. Drug Des Devel Ther 2019; 13:153-60.
7. 7. Walkden GJ, Pickering AE, Gill H. Assessing Long-term Neurodevelopmental Outcome Following General Anesthesia in Early Childhood: Challenges and Opportunities. Anesth Analg 2019; 128:681-94.
8. 8. Costa LG, Aschner M, Vitalone A, et al. Developmental neuropathology of environmental agents. Developmental neuropathology of environmental agents 2004; 44:87-110.

9. 9. Olton DS, Samuelson RJ: Remembrance of places passed: Spatial memory in rats. J Exp Psychol Anim Behav Process 1976; 2:97-116.
10. 10. Wang SQ, Fang F, Xue ZG, et al. Neonatal sevoflurane anesthesia induces long-term memory impairment and decreases hippocampal PSD-95 expression without neuronal loss. Eur Rev Med Pharmacol Sci 2013; 17:941-50.
11. 11. Chen VS, Morrison JP, Southwell MF, et al. Histology Atlas of the Developing Prenatal and Postnatal Mouse Central Nervous System, with Emphasis on Prenatal Days E7.5 to E18.5. Toxicol Pathol 2017; 7:705-44.
12. 12. Briner A, Nikonenko I, De Roo M, et al. Developmental Stage-dependent persistent impact of propofol anesthesia on dendritic spines in the rat medial prefrontal cortex. Anesthesiology 2011; 115:282-93.
13. 13. Sengupta P. The Laboratory Rat: Relating Its Age With Human's. Int J Prev Med 2013; 4:624-30.
14. 14. Satomoto M, Satoh Y, Terui K, et al. Neonatal exposure to sevoflurane induces abnormal social behaviors and deficits in fear conditioning in mice. Anesthesiology 2009; 110:628-37.
15. 15. Kuribayashi J, Sakuraba S, Kashiwagi M, et al. Neural mechanisms of sevoflurane-induced respiratory depression in newborn rats. Anesthesiology 2008; 109:233-42.
16. 16. Zhang Y, Gao Q, Wu Z, et al. Dexmedetomidine Promotes Hippocampal Neurogenesis and Improves Spatial Learning and Memory in Neonatal Rats. Drug Des Devel Ther 2019; 13:4439-49.
17. 17. Hyde LA, Hoplight BJ, Denenberg VH. Water version of the radial-arm maze: learning in three inbred strains of mice. Brain Res 1998; 785:236-44.
18. 18. Pirke KM, Broocks A, Wilckens T, et al. Starvation-induced hyperactivity in the rat: the role of endocrine and neurotransmitter changes. Neurosci Biobehav Rev 1993; 17:287-94.
19. 19. Sagvolden T, Hendley ED, Knardahl S. Behavior of hypertensive and hyperactive rat strains: hyperactivity is not unitarily determined. Physiol Behav 1992; 52:49-57.
20. 20. Shen FY, Song YC, Guo F, et al. Cognitive Impairment and Endoplasmic Reticulum Stress Induced by Repeated Short-Term Sevoflurane Exposure in Early Life of Rats. Front Psychiatry 2018; 2:332.
21. 21. Levin ED. Nicotinic receptor subtypes and cognitive function. J Neurobiol 2002; 53:633-40.
22. 22. Gamoh S, Hashimoto M, Hossain S, et al. Chronic administration of docosahexaenoic acid improves the performance of radial arm maze task in aged rats. Clin Exp Pharmacol Physiol 2001; 28:266-70.
23. 23. Lee JR, Lin EP, Hofacer RD, et al. Alternative technique or mitigating strategy for sevoflurane-induced neurodegeneration: a randomized controlled dose-escalation study of dexmedetomidine in neonatal rats. Br J Anaesth 2017; 119:492-505.
24. 24. Noguchi KK, Johnson SA, Dissen GA, et al. Isoflurane exposure for three hours triggers apoptotic cell death in neonatal macaque brain. Br J Anaesth 2017; 119:524-31.
25. 25. Levin ED. Learning about cognition risk with the radial-arm maze in the developmental neurotoxicology battery. Neurotoxicol Teratol 2015; 52:88-92.
26. 26. Perez-Zoghbi JF, Zhu W, Grafe MR, et al. Dexmedetomidine-mediated neuroprotection against sevoflurane-induced neurotoxicity extends to several brain regions in neonatal rats. Br J Anaesth 2017; 119:506-16.
27. 27. Chen C, Shen FY, Zhao X, et al. Low-dose sevoflurane promotes hippocampal neurogenesis and facilitates the development of dentate gyrus-dependent learning in neonatal rats. ASN Neuro 2015; 7:1759091415575845.
28. 28. Goyagi T. Dexmedetomidine reduced sevoflurane-induced neurodegeneration and long-term memory deficits in neonatal rats. Int J Dev Neurosci 2019; 75:19-26.
29. 29. Duan X, Li Y, Zhou C, et al. Dexmedetomidine provides neuroprotection: impact on ketamine-induced neuroapoptosis in the developing rat brain. Acta Anaesthesiol Scand 2014; 58:1121-6.
30. 30. Endesfelder S, Makki H, von Haefen C, et al. Neuroprotective effects of dexmedetomidine against hyperoxia-induced injury in the developing rat brain. PLoS One 2017; 12:0171498.
31. 31. Perez-Zoghbi JF, Zhu W, Neudecker V, et al. Neurotoxicity of sub-anesthetic doses of sevoflurane and dexmedetomidine co-administration in neonatal rats. Neurotoxicology 2020; 79:75-83.
32. 32. Nakano T, Okamoto H. Dexmedetomidine-induced cerebral hypoperfusion exacerbates ischemic brain injury in rats. J Anesth 2009; 23:378-84.
33. 33. Arakawa H. The effects of isolation rearing on open-field behavior in male rats depends on developmental stages. Dev Psychobiol 2003; 43(1):11-9.
34. 34. Morena M, Berardi A, Peloso A et al. Effects of ketamine, dexmedetomidine and propofol anesthesia on emotional memory consolidation in rats: Consequences for the development of post-traumatic stress disorder. Behav Brain Res 2017; 329:215220.
35. 35. Zhou X, Li W, Chen X, et al. Dose-dependent effects of sevoflurane exposure during early lifetime on apoptosis in hippocampus and neurocognitive outcomes in Sprague-Dawley rats. Int J Physiol Pathophysiol Pharmacol 2016; 8:111-9.
36. 36. Ning Q, Liu Z, Wang X, et al. Neurodegenerative changes and neuroapoptosis induced by systemic lipopolysaccharide administration are reversed by dexmedetomidine treatment in mice. Neurol Res 2017; 39:357-66.
37. 37. Hoffman WE, Kochs E, Werner C, et al. Dexmedetomidine improves neurologic outcome from incomplete ischemia in the rat. Reversal by the alpha 2-adrenergic antagonist atipamezole. Anesthesiology 1991; 75:328-32.
38. 38. Kawakita, K, Funakoshi M. A quantitative study on the tail flick test in the rat. Physiol Behav. 1987; 39:235-40.